BACKGROUND AND PURPOSETRPC1 channels are expressed in the vasculature and are putative candidates for intracellular Ca2+handling. However, little is known about their role in endothelium‐dependent vasodilatations including endothelium‐derived hyperpolarizing factor (EDHF) vasodilatations, which require activation of Ca2+‐activated K+channels (KCa). To provide molecular information on the role of TRPC1 for KCafunction and the EDHF signalling complex, we examined endothelium‐dependent and independent vasodilatations, KCacurrents and smooth muscle contractility in TRPC1‐deficient mice (TRPC1‐/‐).EXPERIMENTAL APPROACHVascular responses were studied using pressure/wire myography and intravital microscopy. We performed electrophysiological measurements, and confocal Ca2+imaging for studying KCachannel functions and Ca2+sparks.KEY RESULTSTRPC1 deficiency in carotid arteries produced a twofold augmentation of TRAM‐34‐ and UCL1684‐sensitive EDHF‐type vasodilatations and of endothelial hyperpolarization to acetylcholine. NO‐mediated vasodilatations were unchanged. TRPC1‐/‐ exhibited enhanced EDHF‐type vasodilatations in resistance‐sized arteriolesin vivoassociated with reduced spontaneous tone. Endothelial IKCa/SKCa‐type KCacurrents, smooth muscle cell Ca2+sparks and associated BKCa‐mediated spontaneous transient outward currents were unchanged in TRPC1‐/‐. Smooth muscle contractility induced by receptor‐operated Ca2+influx or Ca2+release and endothelium‐independent vasodilatations were unaltered in TRPC1‐/‐. TRPC1‐/‐ exhibited lower systolic blood pressure as determined by tail‐cuff blood pressure measurements.CONCLUSIONS AND IMPLICATIONSOur data demonstrate that TRPC1 acts as a negative regulator of endothelial KCachannel‐dependent EDHF‐type vasodilatations and thereby contributes to blood pressure regulation. Thus, we propose a specific role of TRPC1 in the EDHF–KCasignalling complex and suggest that pharmacological inhibition of TRPC1, by enhancing EDHF vasodilatations, may be a novel strategy for lowering blood pressure.